1. Field of the Invention
This invention relates to stable compositions of acidic fentanyl-like drugs and particularly to compositions of fentanyl citrate which are suitable for use in pre-filled syringes.
2. Description of the Prior Art
Fentanyl is the generic name for the compound N-(1-phenethyl-4 piperidyl) propionanilide, a useful injectable analgesic and anesthetic disclosed in U.S. Pat. No. 3,164,600, which is incorporated herein by reference. It has been sold for many years in the United States and elsewhere as the citrate salt under the tradename SUBLIMAZE. Fentanyl has also been sold for many years in the United States and elsewhere in combination with a material whose generic name is droperidol, this combination being sold under the tradename INNOVAR.
Other acidic fentanyl-like compounds include alfentanil, lofentanil, carfentanil, and sufentanil. Other acidic injectable compounds are etomidate and lorcainide. These compounds and others are disclosed in U.S. Pat. Nos. 4,167,574; 3,998,834; 3,354,173; and 4,126,089.
The fentanyl citrate composition sold in the United States comprises fentanyl citrate, USP water for injection, and sufficient sodium hydroxide to raise the pH to 6.5. This prior art composition is referred to throughout this disclosure as the "high pH fentanyl composition". Although this material is reasonably stable in glass ampoules and has been sold in glass ampoules for many years, it has been found unstable when in contact with a rubber closure in (for example) a pre-filled syringe. This instability is sufficiently serious to markedly decrease the potency of this fentanyl composition in a matter of days when contained in conventional syringes.
A different fentanyl citrate composition has been sold in Europe consisting only of fentanyl annd USP water for injection without any deliberate pH adjustment. Because of the specifications for USP water for injection, this composition has a pH in the range of from 5.0 to 7.0. This formulation has also suffered from the same instability with respect to rubber closures as the United States formulation.
INNOVAR is sold as a similar aqueous composition, except that the pH is adjusted to between 3.2 and 3.8. Droperidol (sold by itself under the tradename INAPSINE) is also sold as an aqueous composition having a pH between 3.0 and 3.8.
In the early 1970's, research was conducted on behalf of the company then selling fentanyl to determine the compatibility of a series of rubber closures with the high pH fentanyl citrate composition. This research determined that all 8 closure materials absorbed fentanyl and concluded that "[t]he possibility of packaging Fentanyl Citrate in a container with a rubber closure is rather dim unless the closure is either laquered or film coated or of a material with an extremely non-pourous unreactive surface. The potential for significant loss of drug exists because of the relatively low concentrations of Fentanyl Citrate in solution."
It has now surprisingly and unexpectedly been found that a reduction in the pH of the fentanyl citrate composition from the current 6.5 region to a range of from about 2.0 to about 3.8 yields not only excellent stability in contact with rubber closures but also greatly improved stability in glass ampoules. In fact, the subject low pH fentanyl formulation is more stable in a variety of commercial syringes then is the prior art high pH formulation in glass ampoules. When the low pH composition is stored in glass ampoules, it is virtually unchanged after 18 months at 50.degree. C.
One sort of syringe which is particularly suited to be pre-filled with the subject low pH fentanyl composition is that disclosed and claimed in U.S. Pat. No. 4,367,738, which is incorporated herein by reference.